title: The role of JAK-3 in regulating TLR-mediated inflammatory cytokine production in innate immune cells.
abstract: The role of JAK-3 in TLR-mediated innate immune responses is poorly understood, although the suppressive function of JAK3 inhibition in adaptive immune response has been well studied. In this study, we found that JAK3 inhibition enhanced TLR-mediated immune responses by differentially regulating pro- and anti- inflammatory cytokine production in innate immune cells. Specifically, JAK3 inhibition by pharmacological inhibitors or specific small interfering RNA or JAK3 gene knockout resulted in an increase in TLR-mediated production of proinflammatory cytokines while concurrently decreasing the production of IL-10. Inhibition of JAK3 suppressed phosphorylation of PI3K downstream effectors including Akt, mammalian target of rapamycin complex 1, glycogen synthase kinase 3β (GSK3β), and CREB. Constitutive activation of Akt or inhibition of GSK3β abrogated the capability of JAK3 inhibition to enhance proinflammatory cytokines and suppress IL-10 production. In contrast, inhibition of PI3K enhanced this regulatory ability of JAK3 in LPS-stimulated monocytes. At the transcriptional level, JAK3 knockout lead to the increased phosphorylation of STATs that could be attenuated by neutralization of de novo inflammatory cytokines. JAK3 inhibition exhibited a GSK3 activity-dependent ability to enhance phosphorylation levels and DNA binding of NF-κB p65. Moreover, JAK3 inhibition correlated with an increased CD4(+) T cell response. Additionally, higher neutrophil infiltration, IL-17 expression, and intestinal epithelium erosion were observed in JAK3 knockout mice. These findings demonstrate the negative regulatory function of JAK3 and elucidate the signaling pathway by which JAK3 differentially regulates TLR-mediated inflammatory cytokine production in innate immune cells.
authors.affiliation: Oral Health and Systemic Disease Research Group, University of Louisville School of Dentistry, Louisville, KY 40202, USA. hhwang01@louisville.edu
authors.forename: Huizhi
authors.initials: H
authors.lastname: Wang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Brown
authors.forename: Shegan
authors.initials: S
authors.lastname: Gao
authors.forename: Shuang
authors.initials: S
authors.lastname: Liang
authors.forename: Ravi
authors.initials: R
authors.lastname: Jotwani
authors.forename: Huaxin
authors.initials: H
authors.lastname: Zhou
authors.forename: Jill
authors.initials: J
authors.lastname: Suttles
authors.forename: David A
authors.initials: DA
authors.lastname: Scott
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lamont
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D050882:CREB-Binding Protein / Q000378:metabolism; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology*; D016753:Interleukin-10 / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis; D007413:Intestinal Mucosa / Q000276:immunology; D007422:Intestines / Q000276:immunology; D053616:Janus Kinase 3 / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides; D008213:Lymphocyte Activation / Q000276:immunology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D046912:Multiprotein Complexes / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D051193:Toll-Like Receptors / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism
chemical_list: D050882:CREB-Binding Protein; D004268:DNA-Binding Proteins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D016753:Interleukin-10; D020381:Interleukin-17; D053616:Janus Kinase 3; D008070:Lipopolysaccharides; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D058570:TOR Serine-Threonine Kinases; D051193:Toll-Like Receptors; D051996:Transcription Factor RelA; C498144:Rela protein, mouse; C494364:Crebbp protein, mouse; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse